Integrase inhibitor compounds

Inactive Publication Date: 2007-03-29
GILEAD SCI INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

ependently halo; and [0063] m is zero, one, two, three, four or five. [0064] In still another embodiment, th

Problems solved by technology

Human immunodeficiency virus (HIV) infection and related diseases are a major public health problem worldwide.
Although drugs targeting reverse transcriptase and protease are in wide use and have shown effectiveness, particularly when employed in combination, toxicity and development of resistant strains have limited their usefulness (Palella, etal N. Engl. J.

Method used

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Examples

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example 1

[0519] Intermediates useful in synthesizing compounds of the invention can be prepared by the following methodology. It should be noted that after every step, the product may be recovered and optionally purified by conventional methods such as precipitation, filtration, evaporation, crystallization, chromatography and the like. Alternatively, the products can be used directly in the next step without purification and / or isolation.

[0520] Compound 1 is converted under conventional conditions to the corresponding anhydride 2. Specifically, compound 1 is refluxed in a suitable solvent, such as acetone, methyl ethyl ketone in the presence of an excess of 15 acetic anhydride to provide the anhydride 2. Compound 2 is then refluxed in the presence of an approximately single equivalent of isopropanol for about 2 to about 20 hours to provide for the mono-carboxy, mono-isopropoxy derivative, compound 3. Compound 3 is then condensed under conventional conditions with methylsulfonyl chloride i...

example 2

Preparation of N-(7-(4-fluorobenzyl)-9-hydroxy-8-oxo-7,8-di hydro-6H-pyrrolo[3,4-g]quinolin-5-yl)-N-methylmethanesulfonamide

[0522] Procedure:

[0523] Freshly ground K2CO3 (31 g, 225 mmol) was added to dry acetone (200 mL) in a 3-necked flask equipped with drying tube, condenser, and mechanical stirrer. To this was added succinimide (7.43 g, 75 mmol) and 4-fluorobenzylbromide (11.21 mL, 90 mmol). Refluxed for 19 hours. Mixture filtered through Celite, then acetone removed under vacuum, diluted with EtOAc, washed with saturated aqueous sodium bicarbonate and also with brine, dried (MgSO4), filtered and concentrated to give crude. Crude product chromatographed (EtOAc / hexane) on silica gel to give 6 as white solid (13.22 g, 85%). 1H NMR (CDCI3) δ 7.4 (dd, 2H), 7.0 (t, 2H), 4.6 (s, 1H), 2.7 (s, 4 H).

[0524] Compound 6 (8 g, 38.6 mmol) and 2,3-pyridine carboxylic acid dimethyl ester (7.9 g, 40.6 mmol) were dissolved in dry THF (78 mL) and dry MeOH (1.17 mL) in a 3-necked flask with mecha...

example 5

Preparation of N-(7-(4-fluorobenzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-5-yl)-N,N′,N′-trimethylsulfamide

[0568]

[0569] Intermediate 37 was synthesized from 25 in a manner similar to intermediate 28. Intermediate 37 ( 22 mg, 38 μmol) was dissolved in 200 μL of DCM and treated with TFA (22 mg, 190 μmol) and triethylsilane (9.0 mg, 76 μmol ). After stirring for 15 minutes at room temperature, the reaction mixture was azeotroped with toluene three times. The residue was then triturated with 3:1 hexane:ether to provide 38. 300 MHz 1H NMR (CDCl3) δ (ppm): 9.11 (d, 1H); 8.65 (d, 1H); 7.71 (m, 1H); 7.30 (t, 2H); 7.02 (t, 2H); 4.90 (d, 2H); 4.72 (d, 1H); 4.58 (d, 1H); 4.35 (d, 1H); 3.1 (s, 3H); 2.9 (s, 3H). MS=445.5 ( M +1). Example 6

Alternate Preparation of N-(7-(4-fluorobenzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-5-yl)-N,N′,N′-trimethylsulfamide

[0570]

[0571] To the amine 27 (50 g, 0.099 mmol, 1 eq) contained in a microwave vial was added acetonitrile (2...

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Abstract

Tricyclic compounds, protected intermediates thereof, and methods for inhibition of HIV-integrase are disclosed.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of U.S. Provisional Application 60 / 681,690, filed on May 16, 2005, which is hereby incorporated by reference in its entirety.FIELD OF THE INVENTION [0002] The invention relates generally to compounds having antiviral activity, and more specifically, compounds having HIV-integrase inhibitory properties. BACKGROUND OF THE INVENTION [0003] Human immunodeficiency virus (HIV) infection and related diseases are a major public health problem worldwide. A virally encoded integrase protein mediates specific incorporation and integration of viral DNA into the host genome. Integration is necessary for viral replication. Accordingly, inhibition of HIV integrase is an important therapeutic pursuit for treatment of HIV infection of the related diseases. [0004] Human immunodeficiency virus type 1 (HIV-1) encodes three enzymes which are required for viral replication: reverse transcriptase, protease, and integrase. A...

Claims

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Application Information

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IPC IPC(8): A61K31/4745A61K31/675C07D471/02C07F9/576
CPCC07D471/04C07F9/6561A61P31/18
Inventor CAI, ZHENHONGJABRI, SALMANJIN, HAOLUNKIM, CHOUNGLANSDOWN, RACHAELMETOBO, SAMUELMISH, MICHAELPASTOR, RICHARD
Owner GILEAD SCI INC
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